Myelodysplastic Syndromes and Metabolism

Abstract

Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.

Glycolytic activity and in vitro effect of the pyruvate kinase activator AG‐946 in red blood cells from low‐risk myelodysplastic syndromes patients: A proof‐of‐concept study

“…6 In MDS, a deficiency of mitochondrial subunits or enzymes has been described. 1 Consistently, an increase in extramitochondrial glucose catabolism despite adequate oxygen availability (aerobic glycolysis), namely the Warburg effect, has been observed. This results in the hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1α) through different intermediate metabolites of the tricarboxylic acid cycle, such as the oncometabolite 2-hydroxyglutarate.…”

“…by increased erythron iron turnover along with impaired red blood cell (RBC) utilization, but also by a disrupted metabolism. [1][2][3] Glycolysis is the prominent metabolic cascade in RBCs and is currently targeted with pyruvate kinase (PK) activators in clinical trials in rare anemias. AG-946 is an investigational, small-molecule, potent allosteric activator of PK with the potential to enhance RBC functionality and survival by stimulating glycolysis and to improve differentiation of erythroid cells in bone marrow.…”

“…Possible explanations of metabolic differences between MDS and healthy controls have been linked to the different maturation/proliferation status of MDS stem cells as well as to iron overload and proinflammatory microenvironment in the bone marrow. 1 Erythropoiesis is a highly demanding process, requiring highenergy input obtained through a shift from glycolysis to mitochondrialbased metabolism in normal cells. 6 In MDS, a deficiency of mitochondrial subunits or enzymes has been described.…”

“…This results in the hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1α) through different intermediate metabolites of the tricarboxylic acid cycle, such as the oncometabolite 2-hydroxyglutarate. 1,6 It is worth reminding that iron overload is also associated with a reduction of mitochondrial activity, decreased ATP generation, and increased production of reactive oxygen species (ROS) affecting lipids, DNA, and proteins such as glycolytic enzymes, including glyceraldehyde 3-phosphate dehydrogenase and PK. 6 The above illustrated mechanisms, observed in nucleated bone marrow precursors, may be similar in peripheral MDS-RBCs that mainly rely on glycolysis for ATP production.…”

Hematopoietic Stem Cells (HSC) and Granulocyte Macrophage Progenitors (GMP) are the Oxidative Stress Targets in Low/Intermediate-1 Risk Myelodysplastic Syndromes

“…Also, MDS cells metabolism can be involved in ROS generation. Healthy HSC use glycolysis for energy production while MDS stem and progenitor cells generate energy via oxidative phosphorylation; as a consequence, ROS levels increases [ 33 ]. In the last years, the role of inflammation was investigated in MDS pathogenesis: many studies showed an increase in pro inflammatory cytokines as IL-1β, IL-6, TNFα, and IFN-γ in low risk MDS [ 34 ].…”